This proposal is to study 5-hydroxytryptamine (5-HT, serotonin) receptor- mediated events in the guinea-pig prepositus hypoglossi (PH). The PH nucleus contains a dense serotonergic input, yet has few 5-HT-containing cell bodies, thus constituting a model of a serotonergic terminal field. The methods used will be intracellular and whole-cell electrophysiological recordings from the in vitro brain slice preparation. The central hypothesis is that 5-HT has varying effects on cellular excitability mediated by 5-HT1A, 5-HT2, and 5-HTh receptors. Clinically important compounds such as antidepressants, antimigraine medications, and hallucinogens, may exert some of their therapeutic actions through either acute or chronic effects on these receptors. In the PH, we have observed the following responses: 1) a hyperpolarization due to 5-HT1A activation and a corresponding inhibitory postsynaptic potential (IPSP); 2) a depolarization due to 5-HT2 activation and a corresponding slow excitatory postsynaptic potential; and 3) a depolarization due to 5-HT-induced augmentation of a hyperpolarization-activated current (lh). In addition, we have reported feedback inhibition of the IPSP via a terminal autoreceptor, the 5-HT1D receptor. Each of these responses will be studied with respect to receptor pharmacology, ionic mechanism, and second messenger system. For the 5-HT1A and 5-HT2 responses, the synaptic physiology will be studied including kinetics, interaction with other synaptic events and sensitivity to reuptake inhibitors. In the second phase of this proposal, we will study the acute and chronic effects of clinically important compounds such as fluoxetine, buspirone, sumatriptan, and hallucinogenic amphetamines. These studies will focus particularly on how long term administration may effect the function and sensitivity of 5- HT receptors, their second messengers, and 5-HT reuptake. A concurrent aspect of our studies will be histochemical analysis of PH neurons with respect to cell morphology and co-localization of neurotransmitters. This will clarify the role of 5-HT in the synaptic organization of the PH nucleus.